The unique cytotoxic properties of procarbazine, an effective antitumor agent appear related to its metabolism. Therefore, two major objectives are proposed: 1) a detailed study of the enzymic and non-enzymic degradationof procarbazine and related hydrazines and 2) an investigation of the effects of alkylhydrazine metabolism upon the role of thiols, especially glutathione and the glutathione redox system, in protein synthesis and cell division. Metabolic studies of radiolabeled alkylhydrazines will include development of high pressure liquid chromatography techniques to isolate and identify metabolic intermediates. In vivo, hepatic microsomal and lymphoma cell metabolism of these hydrazines will be compared to determine the origin and nature of the active metabolites(s) of procarbazine. The effects of alkylhydrazine metabolism will be examined principally in implanted murine lymphoma L5178Y ascites cells and in cell culture. Specific effects to be studied include glutathione protein mixed disulfide formation, alteration of hepatic drug metabolism, protein synthesis and alteration of mitotic microtubles protein. 1-Alkyl-2-methylhydrazines are carcinogenic upon long term chronic administration. Experiments are proposed which will examine alterations in drug metabolism, glutathione levels, glutathione redox system and covalent binding of metabolites during long term exposure to hydraxines such as 1,2- dimethylhydraxine and procarbazine. Possible synergistic effects of manganese and thiol agents e.g. diethylmaleate will be examined during these exposures.